Recurrent pregnancy loss (RPL) affects 2-3% of couples. Despite a detailed work-up, the etiology is frequently undefined, leading to non-targeted therapy. Viable embryos and placentae express PreImplantation Factor (PIF). Maternal circulating PIF regulates systemic immunity and reduces circulating natural killer cells cytotoxicity in RPL patients. PIF promotes singly cultured embryos’ development while anti-PIF antibody abrogates it. RPL serum induced embryo toxicity is negated by PIF. We report that PIF rescues delayed embryo development caused by 2 fold the number of embryos reaching the blastocyst stage. Mechanistically, PDI-inhibitor preferentially binds covalently to oxidized PDI over its reduced form where PIF avidly binds. PIF by targeting PDI/TRX at a distinct site limits the inhibitor’s pro-oxidative effects. The >3kDa RPL serum increased embryo demise by three-fold, an effect negated by PIF. However, embryo toxicity was not associated with the presence of putative anti-PIF antibodies. Collectively, PIF protects cultured embryos both against ROS, and higher molecular weight toxins. Using PIF for optimizing in vitro fertilization embryos development and reducing RPL is warranted.

Failed or altered gliogenesis is a major characteristic of diffuse white matter injury in survivors of premature birth. The developmentally regulated long noncoding RNA (lncRNA) H19 inhibits S -adenosylhomocysteine hydrolase (SAHH) and contributes to methylation of diverse cellular components, such as DNA, RNA, proteins, lipids, and neurotransmitters. We showed that the pregnancy-derived synthetic PreImplantation Factor (sPIF) induces expression of the nuclear receptor corepressor 2 (NCOR2) via H19 /SAHH-mediated DNA demethylation. In turn, NCOR2 affects oligodendrocyte differentiation markers. Accordingly, after hypoxic-ischemic brain injury in rodents, myelin protection and oligodendrocytes’ fate are in part modulated by sPIF and H19 . Our results revealed an unexpected mechanism of the H19 /SAHH axis underlying myelin preservation during brain recovery and its use in treating neurodegenerative diseases can be envisioned.

Purpose: To evaluate the role of optimizing the maternal microbiome in improving pregnancy outcomes, focusing on preconception and early gestation, and to propose practical diagnostic and preventive strategies, particularly in low‐ and middle‐income countries (LMIC). Methods: A comprehensive review of peer‐reviewed literature was conducted, analyzing the impact of vaginal, endometrial, gastrointestinal, urinary, and oral microbiomes on fertility and pregnancy. Key factors included microbial dysbiosis, sexually transmitted infections (STIs), and lifestyle interventions. Diagnostic approaches (cultures, gene sequencing) and preventive measures (nutrition, probiotics, vaccinations) were assessed for efficacy in optimizing the microbiome. Results: An optimized microbiome, particularly with Lactobacillus crispatus dominance, enhances fertility and reduces pregnancy complications like miscarriage, preterm birth, and congenital infections. Dysbiosis, linked to obesity, antibiotic overuse, and poor nutrition, increases STI susceptibility and pregnancy risks. Preconception screening and targeted treatments (e.g., antibiotics for STIs, probiotics) improve outcomes. Nutritional interventions, including Mediterranean diets and supplements, support microbial health. LMIC face challenges due to limited access to care and nutrition, exacerbating adverse outcomes to be addressed. Conclusions: Preconception microbiome optimization through diagnostics, lifestyle changes, and targeted therapies significantly improves pregnancy outcomes. Simple, cost‐effective measures are critical also in LMIC to prevent and reduce maternal and fetal morbidity and mortality.